The class of peptide pressor hormone known as angiotensin is responsible for a vasopressor action that is implicated in the etiology of hypertension in man. Inappropriate activity of the renin-angiotensin systems appears to be a key element in essential hypertension, congestive heart failure and in some forms of renal disease. In addition to a direct action on arteries and arterioles, angiotensin II (AII), being one of the most potent endogenous vasoconstrictors known, stimulates the release of aldosterone from the adrenal cortex. Therefore, the renin-angiotensin system, by virtue of its participation in the control of renal sodium handling, plays an important role in cardiovascular homostasis.
Interruption of the renin-angiotensin system with converting enzyme inhibitors, such as captopril, has proved to be clinically useful in the treatment of hypertension and congestive heart failure (Abrams, W. B., et al., (1984), Federation Proc., 43, 1314). The most direct approach towards inhibition of the renin-angiotensin system would block the action of AII at the receptor. Compelling evidence suggests that AII also contributes to renal vasoconstriction and sodium retention that is characteristic of a number of disorders such as heart failure, cirrhosis and complications of pregnancy (Hollenberg, N. K., (1984), J. Cardiovas. Pharmacol., 6, S176). In addition, recent animal studies suggest that inhibition of the renin-angiotensin system may be beneficial in halting or slowing the progression of chronic renal failure (Anderson, S., et al., (1985), J. Clin. Invest., 76, 612). Also, a recent patent application (South African Patent Application Number 87/01,653) claims that AII antagonists are useful as agents for reducing and controlling elevated intraocular pressure, especially glaucoma, in mammals.
The compounds of this invention inhibit, block and antagonize the action of the hormone AII, and are therefore useful in regulating and moderating angiotensin induced hypertension, congestive heart failure, renal failure, glaucoma, and other disorders attributed to the actions of AII. When compounds of this invention are administered to mammals, the elevated blood pressure due to AII is reduced and other manifestations based on AII intercession are minimized and controlled. Compounds of this invention is also expected to exhibit diuretic activity.
Recognition of the importance of blocking and inhibiting the actions of AII has stimulated other efforts to synthesize antagonists of AII. The following references have disclosed imidazole derivatives which are described as having AII blocking activity and useful as hypotensive agents.
U.S. Pat. No. 4,340,598 discloses substituted imidazol-5-yl alkanoic acids, and amido and lower-alkyl ester derivatives thereof, of the formula: ##STR2## wherein R.sup.1 is lower alkyl or phenylC.sub.1-2 alkyl optionally substituted with halogen or nitro; R.sup.2 is lower alkyl, cycloalkyl, or phenyl optionally substituted; one of R.sup.3 and R.sup.4 is --(CH.sub.2).sub.n COR.sup.5, where R.sup.5 is amino, lower alkoxy or hydroxy and n is 0-2, and the other of R.sup.3 and R.sup.4 is hydrogen or halogen. Examples include 1-benzyl-2-n-butyl-4-chloroimidazole-5-acetamide and 1-benzyl-2-n-butyl-5-chloroimidazole-4-acetic acid.
U.S. Pat. No. 4,355,040 discloses substituted 1-benzylimidazol-5-yl acetic acid derivatives having the formula: ##STR3## wherein R.sup.1 is lower alkyl, cycloalkyl, or phenyl optionally substituted; X.sup.1, X.sup.2 and X.sup.3 are each hydrogen halogen nitro, amino, lower alkyl, lower alkoxy, benzyloxy, or hydroxy; Y is halogen and R.sup.2 is hydrogen or lower alkyl. A compound specifically disclosed is 1-(2-chlorobenzyl)-2-n-butyl-4-chloro-imidazole-5-acetic acid.
European Patent Application 103,647 discloses substituted 1-benzyl-2-phenyl-4-chloroimidazol-5-yl acetic acid derivatives of the formula: ##STR4## wherein R is lower alkyl. Specifically, the disclosure includes 4-chloro-1-(4-methoxy-3-methylbenzyl)-2-phenyl-imidazole-5-acetic acid.
European Patent Application 245,637 discloses substituted 4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine derivatives of the formula: ##STR5## wherein - - - is a single or double bond; one of R.sup.1 is present and includes groups such as (CH.sub.2).sub.1-6 naphthyl, (CH.sub.2).sub.1-6 heteroaryl, or (CH.sub.2).sub.1-6 Ph optionally substituted; R.sup.2 includes groups such as hydrogen, lower alkyl, and (CH.sub.2).sub.1-5 Ph; R.sup.3 includes groups such as COC.sub.1-15 alkyl or (CH.sub.2).sub.1-6 Ph optionally substituted; R.sup.4 includes CO.sub.2 R.sup.9, wherein R.sup.9 is hydrogen, lower alkyl or benzyl; and n is 0-3. A compound specifically disclosed is 5-[(4-nitrophenyl)acetyl]-1-(phenylmethyl)-4,5,6,7-tetrahydro-1H-imidazo [4,5-c]pyridine-6-carboxylic acid.
European Patent Application 253,310 discloses substituted 1-aralkylimidazoles having the general formula: ##STR6## wherein R.sup.1 includes groups such as phenyl optionally substituted or adamantylmethyl; R.sup.2 includes groups such as hydrogen, halo, NO.sub.2, C.sub.1-4 alkyl, or C.sub.1-4 alkoxy; R.sup.3 is hydrogen, halo, C.sub.1-4 alkyl, or C.sub.1-4 alkoxy; R.sup.6 includes groups such as C.sub.2-10 alkyl, C.sub.3-10 alkenyl, C.sub.3-8 cycloalkyl, benzyl optionally substituted or Z(CH.sub.2).sub.1-5 --R.sup.5, wherein Z is O or S and R.sup.5 is hydrogen, C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl or alkenyl; R.sup.7 is hydrogen, halo, NO.sub.2, CF.sub.3, or CN, and R.sup.8 includes groups such as C.sub.1-10 alkanoic acids, esters and amides and alkyl N-alkyl carbamates. Examples include 2-n-butyl-5-chloro-1-(4-nitrobenzyl)imidazole-4-acetic acid and 1-[(2'-carboxybiphenyl-4-yl)methyl]-2-n-butyl-4-chloro-5-(dimethylcarbamoy l) imidazole.
Great Britain Patent 1,341,375 describes a series of substituted imidazoles which are useful due to their activity at H-1, H-2 and/or other histamine receptors. The substituted aminoalkylimidazole compounds disclosed therein are of the formula: ##STR7## wherein A is C.sub.1-6 alkyl, optionally substituted by alkyl or aralkyl; R is a substituted or unsubstituted alkyl, aryl or aralkyl group; R.sub.1 is hydrogen alkyl, phenyl, phenylalkyl or imidazolylalkyl; R.sub.20 is hydrogen, alkyl optionally substituted by halo, OH, CN, CO.sub.2 H, NH.sub.2 or CONH.sub.2 ; or COY wherein Y is R.sub.11 O or R.sub.11 NH and R.sub.11 is a substituted or unsubstituted alkyl, aryl, aralkyl or amidino group; and X is 0-3. Examples include N-(2-(4(5)-imidazolyl)ethyl)glycine and 1-benzyl-5-(2-aminoethyl)imidazole.
Woolley, et al., Biochemistry, 48, 709 (1962) relates to 2-benzylhistidine and derivatives thereof as pilots for the synthesis of peptides designed to have specific enzyme activity. Compounds exemplified in this article include 1,2-dibenzylhistidine and N-carbobenzoxy-1,2-dibenzylhistidine.